Work

V1b Receptor Antagonist SSR 149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice

Year: 2017

Type: article

Abstract: BACKGROUND: A recent clinical trial found that pharmacological blockade of V1b receptors reduces alcohol relapse in alcohol-dependent patients. SSR149415 is a selective V1b receptor antagonist that has potential for development as an alcohol dependency treatment. In this study, we investigated whether SSR149415 alone or in combination with the mu-opioid receptor (MOP-r) antagonist naltrexone (NTN) would alter excessive alcohol drinking in mice. METHODS: Both sexes of C57BL/6J (B6) mice were subjected to a chronic intermittent access (IA) drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Sucrose and saccharin drinking were used as controls for alcohol-specific drug effects. Neuronal proopiomelanocortin (POMC) enhancer (nPE) knockout mice with hypothalamic-specific loss of POMC (including beta-endorphin, the main endogenous ligand of MOP-r) were used as a genetic control for the effects of NTN. RESULTS: Acute administration of SSR149415 (1 to 30 mg/kg) reduced alcohol intake and preference in a dose-dependent manner in both male and female B6 mice after IA. To investigate potential synergistic effects between NTN and SSR149415, we tested 6 different combination doses of SSR149415 and NTN, and found that a combination of SSR149415 (3 mg/kg) and NTN (1 mg/kg) reduced alcohol intake profoundly at doses lower than the individual effective doses in both sexes of B6 mice. We confirmed the effect of SSR149415 on reducing alcohol intake in nPE-/- male mice, consistent with independent mechanisms by which SSR149415 and NTN decrease alcohol drinking. CONCLUSIONS: The combination of V1b antagonist SSR149415 with NTN at individual subthreshold doses shows potential in alcoholism treatment, possibly with less adverse effects.

Source: Alcoholism Clinical and Experimental Research

DOI: 10.1111/acer.13544

Authors: Yan Zhou, Marcelo Rubinstein, Malcolm J. Low, Mary Jeanne Kreek

Institutions: Rockefeller University, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, University of Michigan, Michigan Medicine

Language: English

Topic: Neurotransmitter Receptor Influence on Behavior

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute of Diabetes and Digestive and Kidney Diseases